The pancreas secretes insulin, as a blood glucose regulatory hormone, from β cells in accordance with a blood glucose level, and regulates blood glucose. A deficiency of an insulin action causes chronic hyperglycemia, and diabetes accompanied by various characteristic metabolic disorders.
Glucose incorporated into β cells is metabolized to generate various metabolites such as ATP. An ATP sensitive potassium (K+) channel (KATP channel) exists in the β cell. When the KATP channel is closed by ATP generated by the glucose metabolism, a depolarization of a cell membrane, an activation of a voltage-gated calcium (Ca2+) channel, and an increase of an intracellular Ca2+ concentration occur, and then insulin secretory granules are released.
The KATP channel does not function unless eight subunits, i.e., four Kir6.2 subunits and four SUR (Sulphonylurea receptor) subunits, are assembled to construct a channel structure. The KATP channel subunit Kir6.2 is expressed in the pancreas, brain, cardiac muscle, skeletal muscle, and the like, and a complex of Kir6.2 and SUR1 (Sulphonylurea receptor 1) is formed in the pancreas (Inagaki N., Science, 270, 1166–1170, 1995; and Seino S., Diabetes, 49, 311–318, 2000).
In a dominant-negative transgenic mouse with respect to Kir6.2, an increase of a resting membrane potential in pancreatic β cells and an increase of intracellular calcium ion concentration are observed, hyperinsulinism and hypoglycemia are observed (Miki, Proc. Natl. Acad. Sci. USA, 94, 11969–11973).
KATP channel inhibitors cause a depolarization of the cell membrane in β cells, and promote insulin secretion. One of the most popular inhibitors is an SU (Sulphonyl urea) agent which binds to the SUR1 subunit. However, it is known that the SU agent has a problem of secondary failure due to an exhaustion of pancreatic β cells (Groop L., Am. J. Med., 87, 183–190, 1989; Shigeta, Tonyobyo-chiryo-jiten (Dictionary of diabetes treatment), Igaku-syoin, 1996).
In type II diabetes, insulin secretion by a glucose stimulation is generally decreased. However, according to a study using a whole cell recording of patch-clamp methods, in a GK rat as a nonobese type II diabetes model rat (nonobese type II diabetes model obtained by selective breeding of a Wistar rat using a glucose tolerance test as a marker), an activation of a voltage-dependent Ca2+ channel by a depolarization stimulation was induced by comparison with a control (Kato S., J. Clin Invest., 97, 2417–2425, 1996). Further, according to a study using pancreatic islet's of Langerhans treated by a electropermeabilization method, in the GK rat, a sensitivity of secretory granule-releasing system against an increase of an intracellular Ca2+ concentration was induced (Okamoto Y., Diabetologia, 38, 772–778, 1995). Therefore, it is considered that, in type II diabetes, the secretion is maintained or induced with respect to depolarization stimulations other than glucose.